The primary goal of this project is to elucidate the molecular mechanisms by which thyroid hormones[unreadable] regulate the neuromuscular transmission at the vertebrate neuromuscular junction. The proposed studies will[unreadable] address a series of fundamental questions regarding the action of Thyroid hormones (THs) in the[unreadable] mammalian neuromuscular junction (NMJ). The pre- and post-synaptic effects of THs on the mammalian[unreadable] endplate will be characterized. The following 3 aims are proposed:[unreadable] Aim 1. The working hypothesis is that THs control the basal miniature endplate current (MEPC) frequency.[unreadable] In sub-aim 1a, we propose to characterize the acute action of THs on the spontaneous neurotransmitter[unreadable] release from the presynaptic element of the mammalian NMJ. Sub-aim1b, have been designed to[unreadable] characterize the molecular mechanism involved in the non-transcriptional action of THs.[unreadable] Aim 2. We propose that the modification of THs levels cause changes in the spontaneous animal[unreadable] locomotion, which can be explained by peripheral THs' action. We will study how alterations in THs levels[unreadable] produce phenotype modifications (i.e., in spontaneous locomotion, rearing, etc.) in short-term and long-term[unreadable] hypo- and hyperthyroid mice. Furthermore, we will correlate these phenotype modifications with structural[unreadable] variation in the NMJ elements evaluated using confocal microscopy.[unreadable] Aim 3. We hypothesize that THs could interact directly with the postsvnaptic acetvlcholine receptor (AChR)[unreadable] channel. We plan to directly assess this interaction evaluating the activity of the AChR channel in muscle[unreadable] fibers dissociate from Control, hypo- and hyper-thyroid mice using outside-out patches and fast perfusion[unreadable] methodology. [unreadable] These studies extend our previous work to a second phase, in which a variety of approaches developed[unreadable] during the last two years will be applied to define physiological aspects of the effects of THs in mammalian[unreadable] NMJ. Millions of Americans (near 2% of the population) are affected by thyroid dysfunction. There is a[unreadable] disparity between our current understandings of the basic mechanism underlying THs action in the nervous[unreadable] system and the beneficial effects that THs are known to provide.